In a joint statement posted to their Twitter accounts on Monday, they said: “After a great deal of thought and a lot of work, we have made the decision to end our marriage. Over the last 27 years, we have raised three incredible children and built a foundation that works all over the world to enable all people to lead healthy, productive lives.
“We continue to share a belief in that mission and will continue to work together at the foundation, but we no longer believe we can grow together as a couple in this next phase of our lives.
“We ask for space and privacy for our family as we begin to navigate this new life.”
The announcement comes less than two weeks after they made their last public appearance at a virtual COVID-19 event for healthcare workers.
The pair are among some of the richest people in the world, with Bill Gates being the founder of Microsoft, and the pair have a net worth of $130.5 billion (£93.99).
The announcement has lead to speculation about the fortune will be split.
The couple have numerous homes together, a private jet, a luxury art collection and a fleet of cars.
Their assets include a $125million (£90.3 million) compound on the outskirts of Seattle, a seaside mansion in San Diego and a ranch getaway in Santa Fe.
Their divorce will be the largest division of assets since Jeff Bezos and his wife MacKenzie split in 2019.
Signing such a contract will allow them to divide their assets by mutual agreement, rather than going to court.
The contract itself has not been made public.
The pair have said they will continue to work together on their joint foundation, the largest charitable entity in the world.
The Bill and Melinda Gates Foundation was founded in 2000 and has contributed more than $50 billion (£36.01) to a variety of causes, including the eradication of polio and malaria.
The foundation has also invested considerably in coronavirus treatments.
The couple have three children together: Jennifer, 25, Rory, 21, and Phoebe, 18.
The eldest Jennifer spoke out about the divorce announcement on Instagram on Monday afternoon.
She wrote: “I’m still learning how to best support my own process and emotions as well as my family members at this time and am grateful for the space to do so.”